tbuckley/cabot-search huggingface dataset:
Multi-Institutional Melanoma Lymphatic Mapping Experience: The Prognostic Value of Sentinel Lymph Node Status in 612 Stage I or II Melanoma Patients
Authors: Jeffrey E. Gershenwald, William Thompson, Paul F. Mansfield, Jeffrey E. Lee, Maria I. Colome, Chi-hong Tseng, J. Jack Lee, Charles M. Balch, Douglas S. Reintgen, Merrick I. Ross
Journal: Journal of Clinical Oncology (1999)

PURPOSE: To compare the effect of pathologic sentinel lymph node (SLN) status with that of other known prognostic factors on recurrence and survival in patients with stage I or II cutaneous melanoma. PATIENTS AND METHODS: We reviewed the records of 612 patients with primary cutaneous melanoma who underwent lymphatic mapping and SLN biopsy between January 1991 and May 1995 to determine the effects of tumor thickness, ulceration, Clark level, location, sex, and SLN pathologic status on disease-free and disease-specific survival. RESULTS: In the 580 patients in whom lymphatic mapping and SLN biopsy were successful, the SLN was positive by conventional histology in 85 patients (15%) but negative in 495 patients (85%). SLN status was the most significant prognostic factor with respect to disease-free and disease-specific survival by univariate and multiple covariate analyses. Although tumor thickness and ulceration influenced survival in SLN-negative patients, they provided no additional prognostic information in SLN-positive patients. CONCLUSION: Lymphatic mapping and SLN biopsy is highly accurate in staging nodal basins at risk for regional metastases in primary melanoma patients and identifies those who may benefit from earlier lymphadenectomy. Furthermore, pathologic status of the SLN in these patients with clinically negative nodes is the most important prognostic factor for recurrence. The information from SLN biopsy is particularly helpful in establishing stratification criteria for future adjuvant trials.
Statistical Issues and Recommendations for Noninferiority Trials in Oncology: A Systematic Review
Authors: Shiro Tanaka, Yousuke Kinjo, Yoshiki Kataoka, Kenichi Yoshimura, Satoshi Teramukai
Journal: Clinical Cancer Research (2012)

Abstract To provide an overview of noninferiority trials in oncology with a special emphasis on methodologic issues, we conducted a systematic review of randomized trials assessing noninferiority of antineoplastic treatments. We identified 72 articles, of which 65 were randomized phase III trials with a single control arm, 3 were factorial phase III trials, and 4 were randomized phase II trials. Forty-six were trials in lung, colorectal, or breast cancer. The quality of reporting was improved chronologically (P &amp;lt; 0.01); the major deficiencies were claims of noninferiority when the results did not meet statistical criteria for noninferiority (7 articles) or when the noninferiority margin was not prespecified (5 articles). Four trials (6%) presented plans for switching from superiority to noninferiority. The analysis populations were intent to treat (ITT) in 52, per-protocol set (PPS) in 6, and both ITT and PPS in 11 trials. Noninferiority margins were set in 68 trials (94%); 1 trial used both of the conventional and effect retention methods, 17 trials used the conventional method, 5 trials used the effect retention method, and in 45 trials, the method was not specified. Some trials used margins that possibly were larger than the assured effects of the active controls. No trials explicitly took into consideration uncertainty in historical data. Two trials (3%) specified 2 values of margins. Our findings highlight critical deficiencies in design and reporting of noninferiority trials. Seven practical recommendations are presented. Clin Cancer Res; 18(7); 1837–47. ©2012 AACR.
High Expression of HER3 Is Associated with a Decreased Survival in Gastric Cancer
Authors: Mikiko Hayashi, Mikito Inokuchi, Yoko Takagi, Hiroyuki Yamada, Kazuyuki Kojima, Jiro Kumagai, Tatsuyuki Kawano, Kenichi Sugihara
Journal: Clinical Cancer Research (2008)

Abstract Background: The role of human epidermal growth factor receptor (HER) 3 and HER4 has been elucidated in gastric cancer. HER1 and HER2 overexpression are regarded as prognostic factors and targets of treatment. The dimerization of the HER family receptors activates downstream signal pathways and promotes tumor progression. This study investigated the positive correlation between HER1 and HER4 expression and the prognosis of patients with gastric cancers. Experimental Design: Tumor samples were obtained from gastric adenocarcinomas of 134 patients who underwent a gastrectomy from 1999 to 2002. The expression of each HER was analyzed in the tumor by immunohistochemical staining. Parametric correlations were done between HER expression and the clinicopathologic findings. A multivariate analysis was done with the overall survival. Results: HER3 expression was significantly associated with parameters involved with tumor progression, including the depth of tumor invasion (T1 versus T2-T4; P = 0.000), involved lymph nodes (P = 0.000), distant metastasis (P = 0.008), tumor stage (P = 0.000), and recurrent disease (P = 0.000). HER1 was also significantly associated with those factors excluding distant metastasis. A significant relationship was observed between the expression of HER1 and HER3 (P = 0.000). HER3 overexpression was associated with a significantly worse survival (P = 0.0000) and was an independent prognostic factor in the multivariate analysis (hazard ratio, 2.382; 95% confidence interval, 1.009-5.625; P = 0.048). Conclusions: HER3 overexpression is strongly associated with tumor progression and poor prognosis of patients with gastric cancer. It may become a new prognostic factor and a target of treatment.
Mortality in Childhood-Onset Type 1 Diabetes
Authors: Gisela Dahlquist, Bengt Källén
Journal: Diabetes Care (2005)

OBJECTIVE—To describe the age- and sex-specific mortality in a cohort of young type 1 diabetic patients and to analyze the causes of death with special focus on suicide, accidents, and unexplained deaths. RESEARCH DESIGN AND METHODS—A population-based incident childhood diabetes register, covering onset cases since 1 July 1977, was linked to the Swedish Cause of Death Register up to 31 December 2000. The official Swedish population register was used to calculate age- and sex-standardized mortality rates (SMRs), excluding neonatal deaths. To analyze excess risks for specific diagnoses, case subjects were compared with five nondiabetic control subjects, matched by age, sex, and year of death. Death certificates were collected for all case and control subjects. For case subjects with an unclear diagnosis, hospital records and/or forensic autopsy reports were obtained. RESULTS—Mean age- and sex-SMR was 2.15 (95% CI 1.70–2.68) and tended to be higher among females (2.65 vs. 1.93, P = 0.045). Mean age at death was 15.2 years (range 1.2–27.3) and mean duration 8.2 years (0–20.7). Twenty-three deaths were clearly related to diabetes; 20 died of diabetic ketoacidosis. Only two case subjects died with late diabetes complications (acute coronary infarction). Thirty-three case subjects died with a diagnosis not directly related to diabetes; 7 of them committed suicide, and 14 died from accidents. There was no significant difference in traffic accidents (odds ratio 1.02 [95% CI 0.40–2.37]). Obvious suicide tended to be increased but not statistically significantly so (1.55 [0.54–3.89]). Seventeen diabetic case subjects were found deceased in bed without any cause of death found at forensic autopsy. Only two of the control subjects died of similar unexplained deaths. CONCLUSIONS—In a well-developed health care system, there is still a significant excess mortality in young type 1 diabetic patients. We confirm a very large proportion of unexplained deaths in bed, which should be further studied. There is no clear excess death rate caused by suicide or traffic accidents among young diabetic subjects.
Deep Learning-Based Prediction of Right Ventricular Ejection Fraction Using 2D Echocardiograms
Authors: Márton Tokodi, Bálint Magyar, András Soós, Masaaki Takeuchi, Máté Tolvaj, Bálint Károly Lakatos, Tetsuji Kitano, Yosuke Nabeshima, Alexandra Fábián, Mark Bence Szigeti, András Horváth, Béla Merkely, Attila Kovács
Journal: JACC. Cardiovascular imaging (2023)

Evidence has shown the independent prognostic value of right ventricular (RV) function, even in patients with left-sided heart disease. The most widely used imaging technique to measure RV function is echocardiography; however, conventional 2-dimensional (2D) echocardiographic assessment is unable to leverage the same clinical information that 3-dimensional (3D) echocardiography-derived right ventricular ejection fraction (RVEF) can provide.
Patient-reported outcomes and hospitalization data in patients with HER2-positive metastatic breast cancer receiving trastuzumab deruxtecan or trastuzumab emtansine in the phase III DESTINY-Breast03 study
Authors: G. Curigliano, K. Dunton, M. Rosenlund, M. Janek, J. Cathcart, Y. Liu, P.A. Fasching, H. Iwata
Journal: Annals of Oncology (2023)

In the DESTINY-Breast03 clinical trial, trastuzumab deruxtecan (T-DXd) showed superior progression-free survival and overall survival versus trastuzumab emtansine (T-DM1) and manageable safety in patients with human epidermal growth factor receptor 2 (HER2)-positive (HER2+) metastatic breast cancer. Here, patient-reported outcomes (PROs) are reported along with hospitalization data.Patients in DESTINY-Breast03 were assessed for prespecified PRO measures, including European Organization for Research and Treatment of Cancer quality of life (EORTC-QoL) questionnaires [the oncology-specific EORTC Quality of Life Questionnaire Core 30 (QLQ-C30) and breast cancer-specific EORTC QLQ-BR45] and the generic EuroQol 5-dimension 5-level questionnaire (EQ-5D-5L) visual analogue scale. Analyses included change from baseline, time to definitive deterioration (TDD), and hospitalization-related endpoints.EORTC QLQ-C30 baseline global health status (GHS) scores for T-DXd (n = 253) and T-DM1 (n = 260) were similar, with no clinically meaningful change (<10-point change from baseline) while on either treatment (median treatment duration: T-DXd, 14.3 months; T-DM1, 6.9 months). TDD analyses of QLQ-C30 GHS (primary PRO variable) and all other prespecified PROs (QLQ-C30 subscales, the QLQ-BR45 arm symptoms scale, and the EQ-5D-5L visual analogue scale) suggested T-DXd was numerically favored over T-DM1 based on TDD hazard ratios. Of all randomized patients, 18 (6.9%) receiving T-DXd versus 19 (7.2%) receiving T-DM1 were hospitalized, and the median time to first hospitalization was 219.5 versus 60.0 days, respectively.In DESTINY-Breast03, EORTC GHS/QoL was maintained on both therapies throughout treatment, indicating that despite the longer treatment duration with T-DXd versus T-DM1, health-related QoL did not worsen on T-DXd. Furthermore, TDD hazard ratios numerically favored T-DXd over T-DM1 in all prespecified variables of interest including pain, suggesting T-DXd may delay time until health-related QoL deterioration compared with T-DM1. Median time to first hospitalization was three times longer with T-DXd versus T-DM1. Together with reported improved efficacy and manageable toxicity, these results support the overall benefit of T-DXd for patients with HER2+ metastatic breast cancer.
Tracking Multiorgan Treatment Response in Systemic AL-Amyloidosis With Cardiac Magnetic Resonance Derived Extracellular Volume Mapping
Authors: Adam Ioannou, Rishi K. Patel, Ana Martinez-Naharro, Yousuf Razvi, Aldostefano Porcari, David F. Hutt, Francesco Bandera, Tushar Kotecha, Lucia Venneri, Liza Chacko, Paolo Massa, Melissa Hanger, Daniel Knight, Charlotte Manisty, James Moon, Cristina Quarta, Helen Lachmann, Carol Whelan, Peter Kellman, Philip N. Hawkins, Julian D. Gillmore, Ashutosh Wechelakar, Marianna Fontana
Journal: JACC. Cardiovascular imaging (2023)

Systemic light chain amyloidosis is a multisystem disorder that commonly involves the heart, liver, and spleen. Cardiac magnetic resonance with extracellular volume (ECV) mapping provides a surrogate measure of the myocardial, liver, and spleen amyloid burden. The purpose of this study was to assess multiorgan response to treatment using ECV mapping, and assess the association between multiorgan treatment response and prognosis. The authors identified 351 patients who underwent baseline serum amyloid-P-component (SAP) scintigraphy and cardiac magnetic resonance at diagnosis, of which 171 had follow-up imaging. At diagnosis, ECV mapping demonstrated that 304 (87%) had cardiac involvement, 114 (33%) significant hepatic involvement, and 147 (42%) significant splenic involvement. Baseline myocardial and liver ECV independently predict mortality (myocardial HR: 1.03 [95% CI: 1.01-1.06]; P = 0.009; liver HR: 1.03; [95% CI: 1.01-1.05]; P = 0.001). Liver and spleen ECV correlated with amyloid load assessed by SAP scintigraphy (R = 0.751; P < 0.001; R = 0.765; P < 0.001, respectively). Serial measurements demonstrated ECV correctly identified changes in liver and spleen amyloid load derived from SAP scintigraphy in 85% and 82% of cases, respectively. At 6 months, more patients with a good hematologic response had liver (30%) and spleen (36%) ECV regression than myocardial regression (5%). By 12 months, more patients with a good response demonstrated myocardial regression (heart 32%, liver 30%, spleen 36%). Myocardial regression was associated with reduced median N-terminal probrain natriuretic peptide (P < 0.001), and liver regression with reduced median alkaline phosphatase (P = 0.001). Changes in myocardial and liver ECV, 6 months after initiating chemotherapy, independently predict mortality (myocardial HR: 1.11 [95% CI: 1.02-1.20]; P = 0.011; liver HR: 1.07 [95% CI: 1.01-1.13]; P = 0.014). Multiorgan ECV quantification accurately tracks treatment response and demonstrates different rates of organ regression, with the liver and spleen regressing more rapidly than the heart. Baseline myocardial and liver ECV and changes at 6 months independently predict mortality, even after adjusting for traditional predictors of prognosis.
Integrative multi-omics deciphers the spatial characteristics of host-gut microbiota interactions in Crohn’s disease
Authors: Xiang Gao, Ruicong Sun, Na Jiao, Xiao Liang, Gengfeng Li, Han Gao, Xiaohan Wu, Muqing Yang, Chunqiu Chen, Xiaomin Sun, Liang Chen, Wei Wu, Yingzi Cong, Ruixin Zhu, Tiannan Guo, Zhanju Liu
Journal: Cell Reports Medicine (2023)

Dysregulated host-microbial interactions play critical roles in initiation and perpetuation of gut inflammation in Crohn's disease (CD). However, the spatial distribution and interaction network across the intestine and its accessory tissues are still elusive. Here, we profile the host proteins and tissue microbes in 540 samples from the intestinal mucosa, submucosa-muscularis-serosa, mesenteric adipose tissues, mesentery, and mesenteric lymph nodes of 30 CD patients and spatially decipher the host-microbial interactions. We observe aberrant antimicrobial immunity and metabolic processes across multi-tissues during CD and determine bacterial transmission along with altered microbial communities and ecological patterns. Moreover, we identify several candidate interaction pairs between host proteins and microbes associated with perpetuation of gut inflammation and bacterial transmigration across multi-tissues in CD. Signature alterations in host proteins (e.g., SAA2 and GOLM1) and microbes (e.g., Alistipes and Streptococcus) are further imprinted in serum and fecal samples as potential diagnostic biomarkers, thus providing a rationale for precision diagnosis.
A genetically defined tecto-thalamic pathway drives a system of superior-colliculus-dependent visual cortices
Authors: Joshua M. Brenner, Riccardo Beltramo, Charles R. Gerfen, Sarah Ruediger, Massimo Scanziani
Journal: Neuron (2023)

Cortical responses to visual stimuli are believed to rely on the geniculo-striate pathway. However, recent work has challenged this notion by showing that responses in the postrhinal cortex (POR), a visual cortical area, instead depend on the tecto-thalamic pathway, which conveys visual information to the cortex via the superior colliculus (SC). Does POR's SC-dependence point to a wider system of tecto-thalamic cortical visual areas? What information might this system extract from the visual world? We discovered multiple mouse cortical areas whose visual responses rely on SC, with the most lateral showing the strongest SC-dependence. This system is driven by a genetically defined cell type that connects the SC to the pulvinar thalamic nucleus. Finally, we show that SC-dependent cortices distinguish self-generated from externally generated visual motion. Hence, lateral visual areas comprise a system that relies on the tecto-thalamic pathway and contributes to processing visual motion as animals move through the environment.
Application of the Banff Human Organ Transplant Panel to kidney transplant biopsies with features suspicious for antibody-mediated rejection
Authors: Jack Beadle, Artemis Papadaki, Frederic Toulza, Eva Santos, Michelle Willicombe, Adam McLean, James Peters, Candice Roufosse
Journal: Kidney International (2023)

The Banff Classification for Allograft Pathology includes the use of gene expression in the diagnosis of antibody-mediated rejection (AMR) of kidney transplants, but a predictive set of genes for classifying biopsies with 'incomplete' phenotypes has not yet been studied. Here, we developed and assessed a gene score that, when applied to biopsies with features of AMR, would identify cases with a higher risk of allograft loss. To do this, RNA was extracted from a continuous retrospective cohort of 349 biopsies randomized 2:1 to include 220 biopsies in a discovery cohort and 129 biopsies in a validation cohort. The biopsies were divided into three groups: 31 that fulfilled the 2019 Banff Criteria for active AMR, 50 with histological features of AMR but not meeting the full criteria (Suspicious-AMR), and 269 with no features of active AMR (No-AMR). Gene expression analysis using the 770 gene Banff Human Organ Transplant NanoString panel was carried out with LASSO Regression performed to identify a parsimonious set of genes predictive of AMR. We identified a nine gene score that was highly predictive of active AMR (accuracy 0.92 in the validation cohort) and was strongly correlated with histological features of AMR. In biopsies suspicious for AMR, our gene score was strongly associated with risk of allograft loss and independently associated with allograft loss in multivariable analysis. Thus, we show that a gene expression signature in kidney allograft biopsy samples can help classify biopsies with incomplete AMR phenotypes into groups that correlate strongly with histological features and outcomes.
Biodegradable, Self‐Reinforcing Vascular Grafts for In Situ Tissue Engineering Approaches
Authors: Sabrina Rohringer, Christian Grasl, Katharina Ehrmann, Pia Hager, Clemens Hahn, Sophie J. Specht, Ingrid Walter, Karl H. Schneider, Lydia M. Zopf, Stefan Baudis, Robert Liska, Heinrich Schima, Bruno K. Podesser, Helga Bergmeister
Journal: Advanced Healthcare Materials (2023)

Clinically available small-diameter synthetic vascular grafts (SDVGs) have unsatisfactory patency rates due to impaired graft healing. Therefore, autologous implants are still the gold standard for small vessel replacement. Bioresorbable SDVGs may be an alternative, but many polymers have inadequate biomechanical properties that lead to graft failure. To overcome these limitations, a new biodegradable SDVG is developed to ensure safe use until adequate new tissue is formed. SDVGs are electrospun using a polymer blend composed of thermoplastic polyurethane (TPU) and a new self-reinforcing TP(U-urea) (TPUU). Biocompatibility is tested in vitro by cell seeding and hemocompatibility tests. In vivo performance is evaluated in rats over a period for up to six months. Autologous rat aortic implants serve as a control group. Scanning electron microscopy, micro-computed tomography (µCT), histology, and gene expression analyses are applied. TPU/TPUU grafts show significant improvement of biomechanical properties after water incubation and exhibit excellent cyto- and hemocompatibility. All grafts remain patent, and biomechanical properties are sufficient despite wall thinning. No inflammation, aneurysms, intimal hyperplasia, or thrombus formation are observed. Evaluation of graft healing shows similar gene expression profiles of TPU/TPUU and autologous conduits. These new biodegradable, self-reinforcing SDVGs may be promising candidates for clinical use in the future.
Redox modulation with a perfluorocarbon nanoparticle to reverse Treg-mediated immunosuppression and enhance anti-tumor immunity
Authors: Zhaoting Li, Yueyang Deng, Honghao Sun, Caixia Tan, Heming Li, Fanyi Mo, Yixin Wang, Jing Li, Zhanwei Zhou, Minjie Sun
Journal: Journal of Controlled Release (2023)
Tailoring vascular phenotype through AAV therapy promotes anti-tumor immunity in glioma
Authors: Mohanraj Ramachandran, Alessandra Vaccaro, Tiarne van de Walle, Maria Georganaki, Roberta Lugano, Kalyani Vemuri, Despoina Kourougkiaouri, Konstantinos Vazaios, Marie Hedlund, Georgia Tsaridou, Lene Uhrbom, Ilkka Pietilä, Miika Martikainen, Luuk van Hooren, Thomas Olsson Bontell, Asgeir S. Jakola, Di Yu, Bengt Westermark, Magnus Essand, Anna Dimberg
Journal: Cancer Cell (2023)

Glioblastomas are aggressive brain tumors that are largely immunotherapy resistant. This is associated with immunosuppression and a dysfunctional tumor vasculature, which hinder T cell infiltration. LIGHT/TNFSF14 can induce high endothelial venules (HEVs) and tertiary lymphoid structures (TLS), suggesting that its therapeutic expression could promote T cell recruitment. Here, we use a brain endothelial cell-targeted adeno-associated viral (AAV) vector to express LIGHT in the glioma vasculature (AAV-LIGHT). We found that systemic AAV-LIGHT treatment induces tumor-associated HEVs and T cell-rich TLS, prolonging survival in αPD-1-resistant murine glioma. AAV-LIGHT treatment reduces T cell exhaustion and promotes TCF1+CD8+ stem-like T cells, which reside in TLS and intratumoral antigen-presenting niches. Tumor regression upon AAV-LIGHT therapy correlates with tumor-specific cytotoxic/memory T cell responses. Our work reveals that altering vascular phenotype through vessel-targeted expression of LIGHT promotes efficient anti-tumor T cell responses and prolongs survival in glioma. These findings have broader implications for treatment of other immunotherapy-resistant cancers.